The impact of three combinations vildagliptin/metformin, vildagliptin/pioglitazone, and metformin/pioglitazone on glycemic control and atherogenic dyslipidemia in patients with Type 2 diabetes mellitus

Background: There are limitations of currently recommended stepwise treatment for Type 2 diabetes, especially failure with monotherapies to achieve the strict glycemic control. This has prompted the intensification of therapy with such combinations which have additive efficacy and complimentary mechanisms of action. Vildagliptin is one such agent with the above potential which does not increase the risk of hypoglycemia and does not promote weight gain.Methods: It was a prospective, open-label, randomized, and parallel group study involving 90 patients, divided into three Groups A, B, and C. Group A given vildagliptin/metformin (50/500 mg), Group B vildagliptin/pioglitazone (50/15 mg)and Group C metformin/pioglitazone (500/15 mg) combinations twice daily for 12 weeks. Fasting blood glucose (FBG) was estimated biweekly while hemoglobin A1c (HbA1c), lipid profile, insulin, and C-peptide levels at 0 and 12th week. Statistical analysis was done using ANOVA and Student’s t-test.Results: At the end, mean percentage of age fall in HbA1c and FBG from baseline was maximum in Group B, which was found out to be more efficacious than Group A and C (p<0.001) on glycemic parameters. Mean percentage of age decrease in triglyceride from baseline was maximum in Group C, which was found out to be more efficacious than Group A and B (p<0.001) on lipid parameters. The adverse effects were low in all the groups. However, the incidence of peripheral edema and weight gain was more with the use of Group C while nausea, vomiting, and nasopharyngitis was more with the use of Group A.Conclusion: Vildagliptin/pioglitazone combination is of choice in patients with uncontrolled hyperglycemia but normal lipid profile while metformin/pioglitazone combination in diabetic patients with dyslipidemia

Prevalence and haemato-biochemical profile of Anaplasma marginale infection in dairy animals of Punjab (India)

AbstractObjectiveTo do the systematic comparison of prevalence of anaplasmosis by PCR and Giemsa stained thin blood smear (GSTBS) based parasitological assays in dairy cattle of Punjab, which has not been reported yet. To analyse the haematobiochemical alterations in infected animals to arrive at the conclusion regarding the pathogenicity induced by Anaplasma marginale (A. marginale) in latent and patent infection.MethodsStudy was conducted on 320 animals (236 cows, 62 calves and 22 buffaloes) of Punjab, India. PCR on genome of A. marginale was performed by targeting msp1 β gene using specific primers BAP-2/AL34S, amplifies products of size 407 bp. Questionnaires based data on the characteristics of the infected animals and management strategies of the farm were collected and correlated.ResultsHigher prevalence and more significant association was observed in the PCR based molecular diagnosis (P=0.00012) as compared to that in GSTBS (P=0.028 8) based diagnosis with various regions under study. With respect to the regions, highest prevalence was recorded in Ferozepur by PCR based diagnosis, while that in Jalandhar by GSTBS examination. Similar marked significant association of the PCR based diagnosis with the age of the animals under study (P=0.00013) was observed elucidating no inverse age resistance to A. marginale in cow calves. Haematobiochemical profile of infected animals revealed marked anemia, liver dysfunction and increase globulin concentrate indicating rise in immunoglobulin level to counteract infection.ConclusionsPCR is far more sensitive in detecting the disease even in latent infection which may act as nidus for spread of anaplasmosis to susceptible animals in endemic areas. Severity of anaemia and liver dysfunction were comparable both in patent as well as latent infection indicating pathogenicity of both

Observational study for the functional outcome of humerus shaft fractures treated with plating versus nailing

Background: Fractures of the humerus diaphysis comprise approximately 3% of all fractures. It’s treatment has mainly been conservative in the past but is not well tolerated by the patient now a days. Also, all humerus shaft fractures are not amenable to conservative methods. Operative interventions like dynamic compression plating and intramedullary nailing are associated with better functional outcome. There has been a lot of debate on which of the above two surgical methods is better for management of humeral shaft fractures to ensure better functional outcome and lesser complication rate. Objective were to compare the results of the plating and nailing in the treatment of humerus shaft with reference to A) functional outcome and B) complications and their management.Methods: All patients with fracture of humeral shaft presenting to the department of orthopaedics, MMIMSR, during the study period and that met our criteria were included in the study. Out of total 30 patients, 15 were randomly selected for intramedullary nailing and 15 for plating. Postoperatively, these patients were followed up for 6 months and relevant data was collected. Time taken for union, post operative complications rate and final functional outcome were then compared in the two groups. Study design was observational study.Results: It was observed that most of the patient that sustained humeral shaft fractures were 18-40 years of age. Post-operatively, fractures treated by plating united earlier, had lesser complications and significantly better functional outcome compared to nailing.Conclusions: We concluded that plating is a better method and more acceptable to patients as compare to intramedullary nailing for the treatment of fractures shaft humerus, as it is associated with better functional outcome, earlier union of fracture and lesser complication rate

Antenatal risk factors in emergency caesarean sections done for fetal distress

Background: Fetal distress is an important indication for emergency caesarean deliveries. The objective of this study is to identify the antenatal and intrapartum risk factors in emergency caesareans done for non-reassuring fetal status and compare with patients who underwent emergency caesareans for other indications.Methods: It was a retrospective study and data was collected from the labour room records of a tertiary care hospital. Patients undergoing emergency caesareans for fetal distress were the cases and the remaining emergency caesareans were the controls. Data was statistically analyzed.Results: There were 5184 deliveries during this period of which, 669 were emergency caesareans. 126 (18.83%) of these were due to fetal distress/ non-reassuring fetal status and 543 (81.17%) were for other indications. Caesarean due to fetal distress accounted for 2.43% of the total deliveries. There were more primigravidae (61.11% Vs 46.04%) in the fetal distress group (Odds Ratio 1.84, p=0.003). Intra uterine growth restriction (OR 5.44, p<0.0001) and antepartum haemorrhage mainly due to abruption (OR 11.19, p <0.0001) were other important antenatal risk factors. Those with neonates of birth weight between 1.5 to 2.0 kgs were more likely to undergo emergency caesarean for fetal distress (OR 1.78, p=0.0435). The risk of a lower APGAR was higher in the fetal distress group (12.59%). 28.34% neonates in this group required NICU admission.Conclusions: Primiparity, intrauterine growth restriction, antepartum hemorrhage and prematurity, have shown to significantly increase the risk of emergency cesareans due to non-reassuring fetal status. We need to improve antenatal care with a goal of early detection of the above risk factors for timely institution of appropriate intervention and thus contributing to a reduction of emergency caesareans due to fetal distress

How to compare arc-annotated sequences: The alignment hierarchy

International audienceWe describe a new unifying framework to express comparison of arc-annotated sequences, which we call alignment of arc-annotated sequences. We first prove that this framework encompasses main existing models, which allows us to deduce complexity results for several cases from the literature. We also show that this framework gives rise to new relevant problems that have not been studied yet. We provide a thorough analysis of these novel cases by proposing two polynomial time algorithms and an NP-completeness proof. This leads to an almost exhaustive study of alignment of arc-annotated sequences

Mimicry of native peptide antigens by the corresponding retro-inverso analogs is dependent on their intrinsic structure and interaction propensities

Retro-inverso (ri) analogs of model T cell and B cell epitopes were predictively designed as mimics and then assayed for activity to understand the basis of functional ri-antigenic peptide mimicry. ri versions of two MHC class I binding peptide epitopes, one from a vesicular stomatitis virus glycoprotein (VSVp) and another from OVA (OVAp), exhibit structural as well as functional mimicry of their native counterparts. The two ri peptides exhibit conformational plasticity and they bind to MHC class I (H-2Kb) similar to their native counterparts both in silico and in vivo. In fact, ri-OVAp is also presented to an OVAp-specific T cell line in a mode similar to native OVAp. In contrast, the ri version of an immunodominant B cell peptide epitope from a hepatitis B virus protein, PS1, exhibits no structural or functional correlation with its native counterpart. PS1 and its ri analog do not exhibit similar conformational propensities. PS1 is less flexible relative to its ri version. These observed structure-function relationships of the ri-peptide epitopes are consistent with the differences in recognition properties between peptide-MHC vs peptide-Ab binding where, while the recognition of the epitope by MHC is pattern based, the exquisitely specific recognition of Ag by Ab arises from the high complementarity between the Ag and the binding site of the Ab. It is evident that the correlation of conformational and interaction propensities of native L-peptides and their ri counterparts depends both on their inherent structural properties and on their mode of recognition

A role for apoptosis-inducing factor in T cell development

Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report that aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity and a cell-autonomous thymocyte developmental block associated with apoptosis at the β-selection stage, independent of T cell receptor β recombination. No abnormalities are observed in the B cell lineage. Transgenes encoding wild-type or DNA-binding–deficient mutant Aif rectify the thymic defect, but a transgene encoding oxidoreductase activity–deficient mutant Aif does not. The Hq thymic block is reversed in vivo by antioxidant treatment, and Hq T but not B lineage cells show enhanced oxidative stress. Thus, Aif, a ubiquitous protein, serves a lineage-specific nonredundant antiapoptotic role in the T cell lineage by regulating reactive oxygen species during thymic β-selection

Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan

Tc-99m-tamoxifen: A novel diagnostic imaging agent for estrogen receptor-expressing breast cancer patients

PURPOSEThe aim of the study was to radiolabel, characterize, and perform in vitro and in vivo assessment of Technetium-99m (Tc-99m) tamoxifen for screening ER expressing lesions in breast cancer patients.METHODSIn this study, tamoxifen has been radiolabeled with Tc-99m via Tc-99m-tricarbonyl core. The characterization and quality control tests of Tc-99m-tamoxifen were performed. In vitro recep- tor binding and blocking studies were performed in both positive control (MCF-7) and negative control cell lines (MDA-MB-231). Normal biodistribution studies were performed in female Wistar albino rats. The pilot clinical studies were performed in 4 ER-expressing breast cancer patients. Of the 4 patients, 1 was on tamoxifen therapy. All 4 patients had also undergone Fluorine-18 fluorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography.RESULTSTamoxifen was radiolabeled with Tc-99m via Tc-99m-tricarbonyl core with more than 95% radio- chemical yield. Mass spectra showed a peak corresponding to the molecular weight of Tc-99m- tricarbonyl and Tc-99m-tamoxifen. The site of binding of Tc-99m-tricarbonyl with tamoxifen was determined by proton nuclear magnetic resonance. The Tc-99m-tamoxifen showed 30% binding with MCF-7 and only 1%-2% receptor binding with MDA-MB-231 cell lines. Also, the percentage of receptor binding was drastically reduced (up to 72%) when ER was saturated with 50 times the excess molar ratio of unlabeled tamoxifen. In a pilot patient study, Tc-99m-tamoxifen uptake was observed in primary and metastatic lesions. However, no uptake was observed in a patient who was on tamoxifen therapy. The uptake of F-18-FDG was noted in all the patients.CONCLUSIONTamoxifen was radiolabeled with an in-house-synthesized Tc-99m-tricarbonyl core. The radio- labeled complex has been characterized and evaluated for receptor specificity in in vitro and in vivo studies. Also, this is the first clinical study using Tc-99m-tamoxifen for imaging ER. More patients need to be evaluated to further explore the role of Tc-99m-tamoxifen in ER-expressing lesions

Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses

Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes